Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. ALS is most commonly diagnosed in people between 40 and 60 years of age, and men are affected slightly more often than women. One or two out of 100,000 people develop ALS each year and estimated 5,000 people in the United States are diagnosed with the disease each year. ALS is a progressive disease characterized by rapidly progressive weakness, muscle atrophy and fasciculation, spasticity, dysarthria, dysphagia, and respiratory compromise. It is a neurodegenerative movement disorder caused by the degeneration of neurons located in the ventral horn of the spinal cord and the cortical neurons. Unable to function, the muscles weaken and atrophy. Cognitive function is generally spared for most patients although ˜5% also develop frontotemporal dementia. ˜30-50% of patients also show subtle cognitive changes which can be revealed by detailed neuropsychological testing.
There is a known hereditary factor in familial ALS, although this accounts for only around 5-10% of all cases. Approximately 20% of familial cases of ALS have been linked with an autosomal dominant genetic defect on chromosome 21, coding for superoxide dismutase (SOD1). The most common ALS causing SOD1 mutation in North America is A4V, characterized by an exceptionally rapid progression from onset to death. A recent study identified a gene called FUS (“Fused in Sarcoma”, ALS6) as being responsible for 1 in 20 cases of familial ALS.
The degeneration of the first and second motoneuron in ALS is a multifactorial pathologic process. A variety of neuroprotective agents have been examined to counteract initiation and/or progression of disease, but only the glutamate antagonist Riluzole (marketed by Sanofi-Aventis under the trademark Rilutek), which targets glutamate transporters, has reached clinical use so far. It has been found to improve survival to a modest extent and also extends the time before a person needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damage (occurring in ˜10% of people taking the drug). Further known side-effects or Riluzole are nausea and fatigue which may cause patients to discontinue treatment.
Fasudil is a potent Rho-kinase (ROCK) inhibitor and vasodilator. In the past, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke victims. Moreover, it has been found to be useful for the treatment of pulmonary hypertension and to enhance memory and improve the prognosis of Alzheimer patients.
The inventors have previously shown that pharmacological inhibition of rho kinase by Y-27632 (a 4-aminopyridine derivative) and Fasudil (an isoquinoline derivative) does not only enhance regeneration, but also survival of lesioned CNS neurons in vivo and in vitro (Lingor, Teusch et al. 2007; Lingor, Tonges et al. 2008; Planchamp, Bermel et al. 2008; Bermel, Tonges et al. 2009). In addition to the established effects on the actin cytoskeleton, the inventors could show that inhibition of ROCK results in activation of intracellular pathways mediating neuronal survival. Further, the inventors have demonstrated that pharmacologic ROCK inhibition in the optic nerve lesion paradigm leads to a regeneration of lesion optic nerve axons and is able to improve survival of lesioned retinal ganglion cells (Lingor et al. 2010). The neuroprotective potential of ROCK inhibition in neurodegenerative disease has been further corroborated by other groups. For example, an improvement of neurological function and an increase of survival in animal models of Huntington's disease and SMA was reported (Li, Huang et al. 2009; Bowerman, Beauvais et al. 2010). However, a distinct survival prolonging effect in these animals models was only shown in rather acute neurodegenerative models like in the optic nerve lesion paradigm where retinal ganglion cell survival is evaluated 14 days after lesion and in the SMA model in which mice usually die after several weeks of life.
WO 2009/155777 A1 relates to the application of Fasudil in inducing regeneration of stem cells of adult cranial nerves. WO 2005/117896 A1 discloses pharmaceutical formulations of Fasudil and their use in the treatment of inter alia neuronal regeneration.
There is still a need in the art for new and effective treatments of ALS, in particular for treatments having less side-effects than the currently known ones.